Modulation of the brain to affect psychiatric disorders

ABSTRACT

A method for treating neurological conditions by proper placement of a probe and sensing, stimulating or both areas of the brain especially the intralaminar nuclei (ILN”). Moreover, stimulation is controlled and offered when certain conditions within the area of interest are detected. Stimulation and sensing include electrical, chemical or combinations thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of each of U.S. applicationSer. Nos. 09/511,842 now abandoned; 09/511,843 now U.S. Pat. No.6,418,344; 09/511,844 now abandoned; 09/511,845; all filed Feb. 24,2000; and U.S. application Ser. Nos. 09/575,292 now abandoned;09/575,293 now abandoned; 09/574,495 now abandoned all filed May 19,2000.

BACKGROUND OF THE INVENTION

The treatment of psychiatric disorders by surgical means has anextensive history. In the early 1930's, Fulton and Jacobsen firstrecognized that experimentally induced neurotic behavior in chimpanzeescould be abolished by frontal lobectomy. Within a few years, Freeman andWatts developed the first psychosurgical procedure for humans known asthe frontal lobotomy.

As the inherent physiology of the frontal lobe became more evident, theoriginal freehand procedure of Freeman and Watts became less and lessextensive. By the late 1940's, the method of stereotaxis, in which thepatient's brain is modeled in 3-dimensional space for exquisitetargeting accuracy, merged with lesioning techniques resulting in aneven more efficacious and safe psychosurgical procedure. Furtherdevelopments of stereotactic equipment have combined with noveladvancements in functional and anatomic imaging as well asintraoperative electrophysiological mapping to encompass the state ofthe art in the neurosurgical treatment of neurological and psychiatricdisorders today.

While technologically improved and more precise, today's surgicallesioning techniques have the fundamental limitation of being inherentlyirreversible and are essentially a “one shot” procedure with littlechance of alleviating or preventing potential side effects. In addition,there is a limited possibility to provide continuous benefits as thedisease progresses and the patient's symptoms evolve.

Within the field of neurosurgery, the use of electrical stimulation fortreating neurological disease, including such disorders as movementdisorders including Parkinson's disease, essential tremor, dystonia, andchronic pain, has been widely discussed in the literature. It has beenrecognized that electrical stimulation holds significant advantages overlesioning, inasmuch as lesioning can only destroy nervous system tissue.In many instances, the preferred effect is to stimulate to increase,decrease, or block neuronal activity. Electrical stimulation permitssuch modulation of the target neural structures and, equallyimportantly, does not require the destruction of nervous tissue. In manyways, this is analogous to a reversible and adjustable lesioningprocedure.

To date, however, disorders manifesting gross physical dysfunction, nototherwise determinable as having psychiatric and/or behavioral origins,comprise the vast majority of those pathologies treated by deep brainstimulation. A noteworthy example of treatment of a gross physicaldisorder by electrical stimulation is included in the work of AlimBenabid, who developed a method of reducing the tremor associated withParkinson's disease by the application of a high frequency electricalpulse directly to the thalamus. This has also been applied in thesubthalamic nucleus for the treatment of Parkinson's rigidity, slownessof movement, walking and other movement (see e.g. the New EnglandJournal of Medicine, Vol. 339, October 1998, pp. 105-1111, ElectricalStimulation of the Subthalamic Nucleus in Advanced Parkinson's Disease).

Efforts have been made to treat psychiatric disorders withperipheral/cranial nerve stimulation. A recent investigational protocolhas demonstrated partial benefits with vagus nerve stimulation inpatients with depression (Biological Psychiatry 47: 216-286, 2000)Additional clinical trials with depression and vagus nerve stimulationare underway. Another noteworthy example is the effort to controldepression and compulsive eating disorders by stimulation of the vagusnerve is provided in U.S. Pat. No. 5,263,480. This treatment seeks toinduce a satiety effect by stimulating the afferent vagal fibers of thestomach. For patients having weak emotional and/or psychologicalcomponents to their eating disorders, this treatment can be effectiveinsofar as it eliminates the additional (quasi-normal) physio-chemicalstimulus to continue eating. This is especially true for patients whoexhibit subnormal independent functioning of these fibers of the vagusnerve. For compulsive eating patients who are not suffering from aninsufficient level of afferent vagal nerve activity resulting fromsufficient food intake, however, the over stimulation of the vagus nerveand potential resultant over abundance of satiety mediating chemicals(cholecystokinin and pancreatic glucagon) may have little effect. It haseven been suggested that continued compulsive eating, despiteoverstimulation of the vagus nerve, may exacerbate the emotionalcomponent of the patient's disorder. This, therefore, begs the question,is vagus nerve stimulation useful in treating the psychologicalcomponent of the disorder of compulsive eating, or is it simply a methodof minimizing the additional, but natural, pressures to eat because ofnormal physical hunger. More generally, the question may be asked, isperipheral nerve stimulation of any kind the most appropriate method oftreatment for disorders that are, at the core, the result of a pathologyexhibited in the brain. The effect of this peripheral stimulation seemsto be non-specific and a secondary phenomenon. Indeed functional brainimaging studies have demonstrated induction of intracranial thalamicactivity thus providing evidence for an indirect action of theperipheral stimulators. A more appropriate target may be the brainregion which is functioning abnormally.

SUMMARY OF THE INVENTION

Surgical treatments for psychiatric disorders that have traditionallybeen treated by behavioral therapy or psychiatric drugs, have beenlargely limited to the stereotactic lesioning such as cingulotomy,capsulotomy, subcaudate tractotomy, and limbic leucotomy. Suchprocedures have been applied to date in the treatment of affectivedisorders and anxiety disorders. If one critically examines the resultsof these procedures in the literature, it becomes apparent, when appliedto a carefully selected patient population in conjunction with modernstereotactic surgical equipment and imaging techniques, that theseprocedures are both efficacious and safe. In fact, in a certain subsetof patients who have failed all conventional treatments, theseneurosurgical procedures may be the only treatment options available.Therefore, electrical and/or chemical neurosurgical neuromodulatingtechniques, with their inherent reversibility and adjustability, offer asafer and potentially more effective alternative to lesioningprocedures. The present invention relates to modulation of neuronalactivity to affect psychological or psychiatric activity. The presentinvention finds particular application in the modulation of neuronalfunction or processing to affect a functional outcome. The modulation ofnueronal function is particularly useful with regard to the prevention,treatment, or modulation of psychiatric, psychological, behavioral,mood, and thought activity. (unless otherwise indicated these will becollectively referred to herein as “psychological activity” or“psychiatric activity”). When referring to a pathological or undesirablecondition associated with the activity, reference may be made to“psychiatric disorder” or “psychological disorder” instead ofpsychiatric or psychological activity. Although the activity to bemodulated usually manifests itself in the form of a disorder such asaddiction/substance abuse, obsessive compulsive disorder, generalizedanxiety disorder, post traumatic stress disorder, panic attacks, socialphobia, major depression, bipolar disorder, schizophrenia, it is to beappreciated that the invention may also find application in conjunctionwith enhancing or diminishing any neurological or psychiatric function,not just abnormality or disorder. Psychiatric activity that may bemodulated can include, but not be limited to, normal functions such asfear, anger, anxiety, euphoria, sadness, and the fight or flightresponse.

The present invention finds particular utility in its application tohuman psychological or psychiatric activity/disorder. However, it isalso to be appreciated that the present invention is applicable to otheranimals which exhibit behavior that is modulated by the brain. This mayinclude, for example, primates, canines, felines, elephants, dolphins,etc. Utilizing the various embodiments of the present invention, oneskilled in the art may be able to modulate the functional outcome of thebrain to achieve a desirable result.

One technique that offers the ability to affect neuronal function in areversible and dynamic fashion is the delivery of electrical stimulationfor neuromodulation directly to target tissues via an implantedelectrode assembly.

Another technique that offers the ability to affect neuronal function ina reversible and dynamic fashion is the delivery of drugs orneuromodulating chemicals directly to target tissues via asubcutaneously implanted pump and/or a slow release matrix Such drugs,either traditional psychiatric agents or chemicals mimickingneurotransmitters, could be instilled precisely at such low doses as tocompletely avoid the side effects so common to modern pharmacotherapyand to provide a physiological neuromodulation. Such doses could also betailored in magnitude with respect to a particular patient's varyingsymptomatology. A chemical neuromodulating system may also be implantedas a primary treatment strategy or in combination with an electricallybased one.

A combination therapeutic approach, one combining electrical andchemical means, would be penultimate to generating healthy neuronaltissue itself. In addition to the stimulation and chemical modulation,the implantable device could also have chemical and/or electricalsensing functions that can be coupled to the chemical and electricaloutput of the modulating device.

Initially there is an impetus to treat psychiatric disorders with directmodulation of activity in that portion of the brain causing thepathological behavior. In this regard there have been a large number ofanatomical studies that have helped to identify the neural structuresand their precise connections which are implicated in psychiatricactivity/disorders. These are the structures that are functioningabnormally and manifesting in psychiatric/behavioral/addictiondisorders. Numerous anatomical studies from autopsies, animal studies,and imaging such as computerized tomography (CT) scans, and magneticresonance imaging (MRI) scans have demonstrated the role of thesestructures and their connections in psychiatric activity/disorders. Inaddition to these anatomical studies, a number of physiologicaltechniques and diagnostic tools are used to determine the physiologicalaberrations underlying these disorders. This includes electrical methodssuch as electroencephalography (EEG), magnetoencephalography (MEG), aswell as metabolic and blood flow studies such as functional magneticresonance imaging (fMRI), and positron emission tomography (PET). Thecombination of the anatomical and physiological studies have providedincreased insight into our understanding of the structures which areinvolved in the normal functioning or activity of the brain and theabnormal functioning manifesting in psychiatric, behavioral andaddiction disorders.

The primary areas of interest for psychiatric acitivty/disorders includethe pre-frontal cortex, orbitofrontal cortex, anterior limb of theinternal capsule, Nucleus Accumbens, ventral striatum, the ventralPallidum anterior nucleus of the thalamus, dorsomedial nucleus of thethalamus, intralaminar thalamic nuclei, the cingulate cortex, Amygdala,Hippocampus, Mamillary bodies, the lateral hypothlamus the LocusCeruleus, the Dorsal Raphe Nucleus, ventral tegmentum, the SubstantiaNigra Pars Compacta and reticulata. These structures are schematicallyshown in FIGS. 1 and 2 and are implicated in psychiatric activity anddisorders.

One embodiment of the present invention relates generally to modulatingthe pathological electrical and chemical activity of the brain byelectrical stimulation and/or direct placement of neuromodulatingchemicals within the corresponding areas of abnormal function andactivity. In accordance with this embodiment of the present invention, amethod is provided which provides surgical treatment of psychiatricdisorders (e.g. addictions/substance abuse, obsessive compulsivedisorder, generalized anxiety disorder, post traumatic stress disorder,panic attacks, social phobia, major depression, bipolar disorder,schizophrenia, and addictions) by implantation of stimulating electrodesand/or drug/chemical delivery micro infusion at the locations detailedherein.

In another aspect, the present invention also provides methods foridentifying the proper positioning of the electrodes and/orchemical/drug delivery catheters and microinfusion systems within theintralaminar nucleus in the thalamus to affect their associatedconnections in the thalamus and other subcortical and cortical areassuch as the pre-frontal cortex, orbitofrontal cortex, anterior limb ofthe internal capsule, Nucleus Accumbens, ventral striatum, the ventralPallidum, anterior nucleus of the thalamus, dorsomedial nucleus of thethalamus, intralaminar thalamic nuclei, the cingulate cortex, Amygdala,Hippocampus, Mamillary bodies, the lateral hypothlamus the LocusCeruleus, the Dorsal Raphe Nucleus, ventral tegmentum, the SubstantiaNigra Pars Compacta, and reticulata

In one embodiment of the invention, therefore, the proximal end of theelectrode and/or catheter is coupled to an electrical signal sourceand/or drug delivery pump which, in turn, is operated to stimulate thepredetermined treatment site in regions described above such that thefunctional outcome is achieve or the clinical effects of the psychiatricand disorders are reduced.

In an another embodiment of the present invention, a method ofdetermining the proper therapeutic treatment (i.e., the proper positionor placement of the electrodes and/or catheters) for a specificpsychiatric, behavioral, addictive disorder comprising the steps of:identifying a large sampling of patients (each exhibiting a commonspecific psychiatric/addictive disorder or activity) and thenidentifying which common region of the brain exhibits pathologicalelectrical and/or chemical activity during manifestations of thespecific psychiatric disorder. The common regions demonstrating thispathological activity constitute the predetermined treatment site,wherefore a suitable means for affecting the activity of saidpredetermined treatment site may be employed to ameliorate/improve thepsychiatric disorder/activity generically with a high probability ofsuccess.

In particular, the common regions identified above, are hereinidentified by their known anatomical connections and physiologicalfunctioning as being actively involved in channeling or generating thepathological electrical activity associated with psychiatricactivity/disorders. It is important to note that these regions,including their functions and connections, are a common structuralfeature of human brains, and therefore is a common target across a largenumber of patients. As suggested above, this commonality of function andstructure in these structures implicated in the psychiatric activity ordisorder allows for common treatment targeting, even in instanceswherein different patients have other disparate locations within theirbrains that also exhibit pathological electrical and/or metabolicactivity.

In yet another embodiment of the present invention a method of treatinga a specific psychiatric disorder is provided which is comprised ofidentifying the region of the ILN associated/interconnected with theareas (e.g. pre-frontal cortex or basal ganglia) manifesting thepathological electrical activity relating to the specific psychiatricdisorder. These connections are demonstrated more fully in the detaileddescription below and the accompanying Figures. The common regionsdemonstrating this pathological activity constitute the predeterminedtreatment site, wherefore a suitable means for affecting the activity ofsaid predetermined treatment site may be employed to ameliorate thepsychiatric activity/disorder.

In yet another embodiment of the present invention, a method of treatingan addiction associated with an area of interest in a brain comprising:implanting a probe in the area of interest, the probe including achemical sensor and a chemical dispenser; coupling an end of the probein fluid communication with the chemical dispenser to a chemical pump;and sensing in the area of interest a determined chemical condition; andoperating the pump to urge a chemical through the chemical dispenserinto the area of interest to thereby treat the addiction. The step ofsensing may occur at a location distal from the device location, mayoccur at a distant site in the brain epidurally, subdurally, or from thescalp, or may be at the local milieu of the electrode and/ormicroinfusion cannula.

In yet another embodiment of the present invention, a method of treatingan addiction associated with an area of interest in a brain comprising:implanting an electrode in the area of interest of a brain so that adistal end lies in communication with a predetermined site in the areaof interest; coupling a proximal end of the electrode to at least oneremotely located device; sensing electrical activity in the area ofinterest; and operating the electrode to provide electrical stimulationto the area of interest in response to the electrical activity tothereby treat the addiction.

In yet another embodiment of the present invention, a method of treatingan addiction associated with an area of interest in a brain comprising:implanting an electrode in an intralaminar nucleus of a brain so that adistal end lies in communication with a predetermined site in theintralaminar nucleus; coupling a proximal end of the electrode to atleast one remotely located device; sensing electrical activity in thearea of interest; and operating the electrode to provide electricalstimulation to the intralaminar nucleus in response to the electricalactivity to thereby treat the addiction.

In yet another embodiment of the present invention, a method ofdetermining a treatment for, and subsequently treating a specificdisorder comprising: identifying a set of patients, where the patientseach exhibit a common specific disorder; placing a probe relative to abrain of at least one patient from the set of patients so that an end ofthe probe lies in communication with a treatment site in the brain; andoperably connecting a second end of the probe to a remote device, wherethe remote device detects a specified condition in the treatment siteand applies a corrective action based on the detected condition. Thecorrective action may increase thalamic activity or may decreaseactivity in the dorsomedial thalamus. The disorder may be selected fromthe group consisting of anxiety disorder, affective disorder, andsubstance abuse disorder.

In yet another embodiment of the present invention, a method of treatinga disorder associated with a specific area in a brain comprising:implanting a device in contact with an intralaminar nuclei of the brain;sensing activity in a specific area of the brain; and operating thedevice to modulate the intralaminar nuclei in response to said activityto thereby affect the disorder associated with the specific area of thebrain. The stimulation may be electrical, chemical or a combinationthereof. The stimulation may be continuously, intermittently, orperiodically. The specific area of the brain may be different than theintralaminar nuclei. The step of sensing may occur at a location distalfrom the device location, may occur at a distant site in the brainepidurally, subdurally, or from the scalp, or may be at the local milieuof the electrode and/or microinfusion cannula. The specific area may beselected from the group consisting of the pre-frontal cortex,orbitofrontal cortex, anterior limb of the internal capsule, NucleusAccumbens, ventral striatum, the ventral Pallidum anterior nucleus ofthe thalamus, dorsomedial nucleus of the thalamus, intralaminar thalamicnuclei, the cingulate cortex, Amygdala, Hippocampus, Mamillary bodies,the lateral hypothlamus the Locus Ceruleus, the Dorsal Raphe Nucleus,ventral tegmentum, the Substantia Nigra Pars Compacta and reticulata.The psychiatric disorders may be selected from the group consisting ofobsessive compulsive disorder, generalized anxiety disorder, posttraumatic stress disorder, panic attacks, social phobia, majordepression, bipolar disorder, schizophrenia, and substance abusedisorders/addictions.

In yet another embodiment of the present invention, a method ofaffecting a specific area in a brain comprising: placing an electrode incontact with an intralaminar nuclei of the brain; and operating thedevice to provide stimulation to the intralaminar nuclei to therebyaffect the specific area of the brain. The stimulation may beelectrical, chemical or a combination thereof. The stimulation may becontinuously, intermittently, or periodically. The specific area of thebrain may be different than the intralaminar nuclei. The step of sensingmay occur at a location distal from the device location, may occur at adistant site in the brain epidurally, subdurally, or from the scalp, ormay be at the local milieu of the electrode and/or microinfusioncannula. The specific area may be selected from the group consisting ofthe pre-frontal cortex, orbitofrontal cortex, anterior limb of theinternal capsule, Nucleus Accumbens, ventral striatum, the ventralPallidum anterior nucleus of the thalamus, dorsomedial nucleus of thethalamus, intralaminar thalamic nuclei, the cingulate cortex, Amygdala,Hippocampus, Mamillary bodies, the lateral hypothlamus the LocusCeruleus, the Dorsal Raphe Nucleus, ventral tegmentum, the SubstantiaNigra Pars Compacta and reticulate. The psychiatric disorders may beselected from the group consisting of obsessive compulsive disorder,generalized anxiety disorder, post traumatic stress disorder, panicattacks, social phobia, major depression, bipolar disorder,schizophrenia, and substance abuse disorders/addictions.

In yet another embodiment of the present invention, a method ofeffecting psychiatric activity in a patient comprising: identifying aportion of the patient's ILN which is in communication with apredetermined region of the patient's brain, said predetermined regionof said patient's brain being associated with the psychiatric activity;and modulating the portion of the patient's ILN to effectuate thepsychiatric activity. The identification of a portion of the patient'sILN may already be identified. The identifying step may be independentof an exhibition of a pathologic condition in the predetermined regionof said patient's brain. The psychiatric activity may be selected fromthe group consisting of happiness, fear, anger, anxiety, euphoria, andsadness. The modulation of the portion of the patient's ILN isaccomplished using chemical stimulation, electrical stimulation, orcombinations thereof.

Still further aspects of the present invention will become apparent tothose of ordinary skill in the art upon reading and understanding thefollowing detailed description of the preferred embodiments.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention may take form in various components and arrangements ofcomponents and in various steps and arrangements of steps. The drawingsare only for purposes of illustrating the preferred embodiments and arenot to be construed as limiting the invention.

FIG. 1 is a side view of the brain with an implanted electrical/chemicaldelivery and sensing device illustrating components of the braininvolved in psychiatric activity and disorders;

FIG. 2 schematically illustrates the various structures of the brain andtheir inter-connections involved with the neural circuitry ofpsychiatric activity/disorders;

FIG. 3 illustrates the layout and orientation of the intralaminar nuclei(“ILN”) including the position of the related subdivisions and nucleiwith respect to the thalamus;

FIG. 4 illustrates the ILN nuclei and their interconnections to thevarious structures involved in the psychiatric circuitry;

FIG. 5 is a table providing coordinates of various regions of the brain;and

FIG. 6 is a table providing coordinates of various regions of the ILN.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

While the present invention will be described more fully hereinafterwith reference to the accompanying drawings, in which particularembodiments are shown, it is to be understood at the outset that personsskilled in the art may modify the invention herein described whileachieving the functions and results of this invention. Accordingly, thedescriptions which follow are to be understood as illustrative andexemplary of specific structures, aspects and features within the broadscope of the present invention and not as limiting of such broad scope.

U.S. Pat. No. 6,167,311 to Rezai, U.S. Pat. No. 5,938,688 to Schiff, andU.S. Pat. Nos.: 5,782,798; 5,975,085; 6,128,537; and 6,263,237 to Riseare all incorporated herein in their entirety by reference thereto.

One aspect of the present invention comprises a method of identifyingpatients with psychiatric disorders. This process begins with theaccumulation of physical, chemical, and historical behavioral data oneach patient. A collection of patients who have been identified asexhibiting similar clinical symptoms are then grouped together andsubject to a series of common non-invasive brain imaging studies.

One important aspect of the present invention is the recognition that itis desirable to affect psychiatric activity and disorders withmodulation of activity in that portion of the brain causing theabnormality or in the related circuitry. Anatomical studies fromanimals, autopsies as well as MRI and CT imaging have been correlated todetermine the structures and their connections which are implicated inpsychiatric disorders.

A variety of techniques can be used to determine normal and abnormalbrain function that can result in disorders. Functional brain imagingallows for localization of specific normal and abnormal functioning ofthe nervous system. This includes electrical methods such aselectroencephalography (EEG), magnetoencephalography (MEG), as well asmetabolic and blood flow studies such as functional magnetic resonanceimaging (fMRI), and positron emission tomography (PET) which can beutilized to localize brain function and dysfunction. The complimentaryfeatures of these techniques allows one to routinely and reproduciblylocalize and detect brain function and dysfunction to be localized.

The use of magnetoencephalography (MEG scans) has permittedquantification of electrical activity in specific regions of the brain.It has been proposed that MEG scans may be used to identify regionsexhibiting pathological electrical activity. However, simply identifyingthe regions of the brain which are exhibiting pathological electricalactivity for a specific patient may not be sufficient to generalizeacross a large population of patients, even if they are exhibitingidentical disorders. The correlation of specific areas of the brain thatare not demonstrating normal activity across a group of patientsexhibiting similar clinical symptoms and who are similarly diagnosedshould not be assumed a priori.

FIG. 1 illustrates a side view of a human brain having a stimulationelectrode implanted in a pre-determined region of the brain (e.g. thethalamus) in accordance with one aspect of the present invention. ThisFig. demonstrates the major overall structures implicated in thepsychiatric activity and disorders. This includes the orbitofrontalcortex (201), thalamus (202), prefrontal cortex (203), putamen andglobus pallidus (204), caudate (205), amygdala (206) and cingulatecortex (207). These structures are interlinked via precise circuits. Forexample, the thalamus has over 100 subsections, some of which areimplicated in psychiatric disorders (see below). The details of howthese structures interplay are described below.

The structures and their connections/projections, which are implicatedin the circuitry of psychiatric activity and disorders, are shown inFIG. 2. As shown in the in FIG. 5 these structures and their X(Medial-lateral), Y (anterior-posterior) and Z (superior-inferior)stereotactic coordinates with respect to the anterior commissure (AC)and the posterior commissure (PC) are identified.

Much of the teaching below will focus on the specific placement of theneuromodulation device within the various neuronal structures and theirconnections which are implicated in psychiatric disorders(psychological, behavioral, addictive/substance abuse and developmentaldisorders including obsessive compulsive disorder, generalized anxietydisorder, post traumatic stress disorder, panic attacks, social phobia,major depression, bipolar disorder, schizophrenia, addictions autism,dyslexia). These structures include the pre-frontal cortex,orbitofrontal cortex, anterior limb of the internal capsule, NucleusAccumbens, ventral striatum, the ventral Pallidum anterior nucleus ofthe thalamus, dorsomedial nucleus of the thalamus, intralaminar thalamicnuclei, the cingulate cortex, Amygdala, Hippocampus, Mamillary bodies,the lateral hypothlamus the Locus Ceruleus, the Dorsal Raphe Nucleus,ventral tegmentum, the Substantia Nigra Pars Compacta and reticulata .Those of ordinary skill in the art understand that the teachings hereare broadly applicable to treating disorders anywhere in the brain.

Once a patient has been identified as exhibiting abnormal clinicalbehavior symptomatic of one of these disorders, subsequent pre-operativebrain imaging scans are used to support the presumption that theabnormal signals associated with the disorder are being channeledthrough one of these related regions and then surgical intervention withelectrical and/or chemical stimulation is taken.

Different aspects of the present invention comprise new and novelmethods of treating disorders by implantation of probes into specificarea of the brain. It is to be understood that the term probes, as usedhere, is meant to include stimulation electrodes, drug-deliverycatheters, sustained release matrixes, electrical sensors, chemicalsensors or combinations of any of these at specific locations. Theselocations will be discussed in detail below.

In one aspect of the invention, therefore, the proximal end of the probeis coupled to an electrical signal source, drug delivery pump, or bothwhich, in turn, is operated to stimulate the predetermined treatmentsite in the brain structures such as pre-frontal cortex, orbitofrontalcortex, anterior limb of the internal capsule, Nucleus Accumbens,ventral striatum, the ventral Pallidum anterior nucleus of the thalamus,dorsomedial nucleus of the thalamus, intralaminar thalamic nuclei, thecingulate cortex, Amygdala, Hippocampus, Mamillary bodies , the lateralhypothlamnus the Locus Ceruleus, the Dorsal Raphe Nucleus, ventraltegmentum, the Substantia Nigra Pars Compacta and reticulata such thatthe clinical effects of the psychiatric disorder are reduced.

In particular, the pre-frontal cortex, orbitofrontal cortex, anteriorlimb of the internal capsule, Nucleus Accumbens, ventral striatum, theventral Pallidum anterior nucleus of the thalamus, dorsomedial nucleusof the thalamus, intralaminar thalamic nuclei, the cingulate cortex,Amygdala, Hippocampus, Mamillary bodies, the lateral hypothlamus theLocus Ceruleus, the Dorsal Raphe Nucleus, ventral tegmentum, theSubstantia Nigra Pars Compacta and reticulata are herein identified bytheir known anatomical connections and functional brain imaging as beingactively involved in channeling or gating the pathological electricaland/or metabolic activity associated with psychiatric disorders. It isimportant to note that these regions and functions, and its connectionsare common structural features of human brains, and therefore is acommon target across a large number of patients.

In another aspect, the present invention comprises a method ofdetermining the proper therapeutic treatment, e.g., the proper positionor placement of the electrodes, for a specific psychiatric disordercomprising the steps of identifying a large sampling of patients, eachexhibiting a common specific psychological disorder and then identifyingwhich common region or nuclei exhibits pathological electrical activityduring manifestations of the specific disorder. The common regionsdemonstrating this pathological activity constitute the predeterminedtreatment site, wherefore a suitable means for affecting the activity ofsaid predetermined treatment site might be employed to ameliorate thepsychiatric disorder generically with a high probability of success.

Additionally, however, the instruments utilized in guiding the surgeonin placing the actual electrodes into these structures have a similardegree of variability, or limit of resolution. Fortunately, the state ofthe art in surgical intervention and the resilience of the brain tissuepermits a small degree of manipulation of the electrode once it isinserted. In fact, a number of advanced electrode designs have beenpresented which permit the micromanipulation of each of the electricalcontacts' position without macromanipulation of the overall electrode.

Surgical intervention comprises the second stage of the treatment.Standard neurosurgical techniques for implantation of a probe may beutilized. It shall be understood that the implantation of electrodes,catheters, sensors or any combination both into various implicatedstructures of the brain (pre-frontal cortex, orbitofrontal cortex,anterior limb of the internal capsule, Nucleus Accumbens, ventralstriatum, the ventral Pallidum anterior nucleus of the thalamus,dorsomedial nucleus of the thalamus, intralaminar thalamic nuclei, thecingulate cortex, Amygdala, Hippocampus, Mamillary bodies, the lateralhypothlamus the Locus Ceruleus, the Dorsal Raphe Nucleus, ventraltegmentum, the Substantia Nigra Pars Compacta and reticulata) is withinthe skill of one ordinarily skilled in the art. It is the application ofthis technique for the treatment of disorders generally and psychiatricdisorders specifically being addressed herein. This technique,therefore, is as follows.

Patients who are to have a probe implanted into the brain, first have astereotactic head frame, such as the Leksell, CRW, or Compass, mountedto the patient's skull by fixed screws. Subsequent to the mounting ofthe frame, the patient undergoes a series of magnetic resonance imagingsessions, during which a series of two dimensional slice images of thepatient's brain are built up into a quasi-three dimensional map invirtual space. This map is then correlated to the three dimensionalstereotactic frame of reference in the real surgical field. In order toalign these two coordinate frames, both the instruments and the patientmust be situated in correspondence to the virtual map. The head frame istherefore rigidly mounted to the surgical table. Subsequently, a seriesof reference points are established relative aspects of the frame andpatient's skull, so that the computer can adjust and calculate thecorrelation between the real world of the patient's head and the virtualspace model of the patient MRI scans. The surgeon is able to target anyregion within the stereotactic space of the brain with precision (e.g.within 1 mm). Initial anatomical target localization is achieved eitherdirectly using the MRI images, or indirectly using interactiveanatomical atlas programs that map the atlas image onto the stereotacticimage of the brain. The various anatomical targets in stereotactic X, Y,and Z coordinates are listed in the tables in FIGS. 5 and 6.

The surgery itself can be performed under either local or generalanesthetic. An initial incision is made in the scalp, preferably 2.5centimeters lateral to the midline of the skull, anterior to the coronalsuture. A burr hole is then drilled in the skull itself; the size of thehole being suitable to permit surgical manipulation and implantation ofthe electrode. This size of the hole is generally about 14 millimeters.The dura is then opened, and fibrin glue is applied to minimize cerebralspinal fluid leaks and the entry of air into the cranial cavity. A guidetube cannula with a blunt tip is then inserted into the brain parechymato a point approximately one centimeter from the target tissue. At thistime physiological localization starts with the ultimate aim ofcorrelating the anatomical and physiological findings to establish thefinal stereotactic target structure.

Physiological localization using single-cell microelectrode recording ispreferable for definitive target determination. Sole reliance onanatomical localization can be problematic because of the possiblediscrepancies between the expected location (expected from thevisualization provided by the virtual imaging of the MRI) and the actualposition within the skull. Microelectrode recording provides exquisitephysiological identification of neuronal firing patterns via directmeasures of individual single unit neuronal activity. Single-cellmicroelectrode recordings obtained from intralaminar thalamic cellstypically have a characteristic bursting activity. In addition tomicroelectrode recording, microstimulation and or macrostimulation maybe performed to provide further physiological localization.

Once the final target nucleus has been identified in the real spatialframe of reference, the probe is implanted. General principles guidingthe final implantation of a probe involve the placement of the probe ina region, and in an orientation, allowing for maximal efficacy whileminimizing the undesired side effects. The currently used brainstimulating electrodes are preferably quadripolar electrodes. Theelectrode itself is generally approximately 1-1.5 millimeter diameterflexible elastomeric sheath that contains four wound wire leads. Theleads terminate at the distal and proximal ends of the sheath in fourelectrically insulated cylindrical contact pad. The contact pads at thedistal end are less than 2 millimeters in length and are separated by aninsulating distance, for example between 0.5 and 2 millimeters. At theproximal end, which is anywhere from 25 to 50 centimeters distance fromthe distal end, a corresponding series of contacts are provided so thatthe electrode may be coupled to a potential source, or to a couplinglead which permits remote disposition of the signal source.

When used, the drug delivery catheter is generally a silastic tubesimilar to the one used in the intrathecal drug delivery systemscommonly in use. With regard to catheter placement, care is taken not toplace the catheter directly within a vascular structure. This can beachieved by combining data from conventional and/or magnetic resonanceangiography into the stereotactic targeting model. The distal portion ofthe catheter has multiple orifices to maximize delivery of the agentwhile minimizing mechanical occlusion. The proximal portion of thecatheter can be connected directly to a pump or via a metal, plastic, orother hollow connector, to an extending catheter.

When used, the sustained release matrix may be utilized independently todeliver a controlled amount of a pharmaceutical or other agent to thespecific area of the brain or the intralaminar nuclei of the brain. Thesustained release matrix design for stents may be used as an example ofa means to deliver a drug at the site of contact, as disclosed forexample in U.S. Pat. No. 5,102,417 (Palmaz), in International PatentApplication Nos. WO 91/12779 (Medtronic, Inc.), and in WO 90/13332(Cedars-Sanai Medical Center), which are all hereby incorporated intheir entirety by be reference thereto. The sustained release matrix maybe used in combination with a lead/electrode to provide electricalstimulation and chemical stimulation. In this scenario, as discussed inmore detail in U.S. Pat. No. 6,256,542 which is hereby incorporated inits entirety by reference thereto, the distal end of the assembly is thedistal or tip electrode which is provided with an elongated proximallyextending shank around which the tine sleeve is mounted. The shankportion of the electrode contains a proximal facing bore in which amonolithic controlled release device is located, containing an agent ordrug compounded into a plastic matrix, for example as disclosed in U.S.Pat. No. 4,972,848 issued to DiDomenico or U.S. Pat. No. 4,506,680issued to Stokes, both incorporated herein by reference in theirentireties.

The initial application of the electrical signal through the electrodeis then attempted. The electrical signal source is activated therebyapplying an oscillating electrical signal, having a specified pulsewidth. The oscillating electrical signal may be applied continuously orintermittently. One can adjust the stimulating poles, the pulse width,the amplitude, as well as the frequency of stimulation to achieve adesired goal. The application of the oscillating electrical signal maystimulate/increase or block/decrease the neuronal and axonal activity.The frequency of this oscillating electrical signal is then adjusteduntil the physiological disorder being treated has been demonstrablyalleviated. This is then considered the ideal frequency. Once the idealfrequency has been determined, the oscillating electrical signal ismaintained at this ideal frequency. Preferably, the oscillatingelectrical signal is operated at a voltage between about 0.1 μV to about20 V. More preferably, the oscillating electrical signal is operated ata voltage between about 0.1 V to about 20 V. Preferably, the electricsignal source is operated at a frequency range between about 2 Hz toabout 2500 Hz. More preferably, the electric signal source is operatedat a frequency range between about 2 Hz to about 200 Hz. Preferably, thepulse width of the oscillating electrical signal is between about 10microseconds to about 1,000 microseconds. More preferably, the pulsewidth of the oscillating electrical signal is between about 50microseconds to about 500 microseconds. Preferably, the application ofthe oscillating electrical signal is: monopolar when the electrode ismonopolar, bipolar when the electrode is bipolar, and multipolar whenthe electrode is multipolar. Preferably the electrode is an implantablemultipolar electrode with either an implantable pulse generator that canbe under patient control or a radio frequency controlled device operatedby an external transmitter.

The OFC is illustrative of the benefits of the present invention. TheOFC has direct and reciprocal excitatory connections, presumablymediated by the neurotransmitter glutamate, with the dorsomedial andanterior thalamic nuclei. In addition, a more indirect loop existsbetween the OFC, the dorsomedial thalamic nucleus, the ventromedialstriatum, and the globus pallidus. Multiple connections also existbetween the OFC and the limbic system. The limbic system is a group ofstructures in the brain, which are thought to mediate the emotionalstate. At the core of this system is the Papez circuitwhich includes thecingulate gyrus, the anterior thalamic nucleus, the amygdala, thefornix, and the mamillary bodies. The OFC has numerous connections withthe Papez circuit via the baslolateral amygdala, the anterior thalmicnucleus and the anterior cingulate gyrus.

There are two coordinated loops passing through the basal ganglia to thethalamus. One, a “motor” loop centered on the sensorimotor,caudate/putamen, globus pallidus, thalamus, and premotor areas. Thesecond “associative” loop involves cortical association areas, caudate/putamen, globus pallidus, subthalamic nucleus and substantia nigra.Based on this framework, the modern neurosurgical intervention inParkinson's disease (PD) has been developed

While movement disorders, chronic pain, and psychiatric disease mightseem as dissimilar entities on the surface, they share common neuralsubstrates. From the earliest observations of OCD, the central role ofneuronal areas subserving motor function in its pathogenesis has beenspeculated. Indeed, Freud himself proposed that the neurologic substratefor the OCD patient's ego lies “at the motor end of the psychicalsystem.” Tourette's Disorder, a disease characterized by motor tics aswell as OCD-like symptoms demonstrates the phenomenon of a neuralsubstrate capable of producing motor as well as psychiatric diseasestates. Studies demonstrating the strong clinical and geneticassociation between Gilles de la Tourette syndrome and OCD havesuggested the central role of the basal ganglia in the genesis of OCDsymptoms. A similar basal ganglia circuit to the one implicated inParkinson's Disease has been proposed to explain the production of bothmotor and obsessional symptoms in Tourette's Disorder. Further analysisof the clinical spectrum of Parkinson's disease has revealed manystriking similarities between the “motor” disease of PD and thepsychiatric diseases of OCD and Affective Disorder.

Based on these observations, coupled with the serotonergic hypothesis ofOCD pathogenesis, a neuronal architecture for the basis of OCD has beenproposed. This model hypothesizes that the primary pathogenic mechanismlies in a dysregulation of the basal ganglia/limbic striatal circuitsthat modulate neuronal activity in and between posterior portions of theorbitofrontal cortex and the medial, especially dorsomedial, thalamicnuclei

There are several components to this neuronal model of OCD. The firstcomponent involves a reciprocal positive-feedback loop involving theorbitofrontal cortex and the dorsomedial thalamic nucleus, by way of theanterior limb of the internal capsule. The corticothalamic projection isexcitatory and mediated primarily by glutamate and aspartate. Althoughthe reciprocal thalamocortical projection's neurotransmitter remains tobe identified, multiple studies suggest it to be excitatory as well.

The second component of the OCD model involves the orbitofrontal cortex,the ventral striatum, the ventral pallidum, and the dorsomedial nucleus.While the transmissions of the ventral striatum to the ventral palliduminvolve multiple neurotransmitters including Gamma aminobutyric acid(GABA) and substance P, the output of this pathway by way of the ventralpallidum to the thalamus is almost exclusively inhibitory, mediated byGABA. This component is thought to serve as a modulator for theexcitatory positive-feedback orbitofrontal thalamic loop describedearlier. Another vital aspect of this second component of the OCD modelinvolves serotonergic projections from the dorsal raphe nuclei of themidbrain to the ventral striatum. These are speculated to be inhibitoryin nature.

The dorsomedial nucleus also has connections to the limbic system. Thelimbic system is a group of structures in the brain, which are thoughtto mediate the emotional state. At the core of this system is the Papezcircuit, which includes the cingulate gyrus, the anterior thalamicnucleus, the amygdala, the fornix, and the mamillary bodies. Thedorsomedial thalamic nucleus has been shown to have connections with thebasolateral amygdala.

The third component of this model involves the limbic system and thecircuit of Papez. At its core, OCD is an anxiety disorder, and theimpact of the patient's various obsessions/compulsions on his/heremotional state is the hallmark of the disease. Papez concluded thatparticipation from the cerebral cortex is essential for the subjectiveemotional experience and that emotional expression is dependent on theintegrative action of the hypothalamus. Papez devised a circuit based onhis observations on neuroanatomic connections to integrate these twostructures. The pathway begins from the hippocampal formation to themammillary body via the fornix. The projection, via the mammillothalamictract, continues on to the anterior thalamic nuclei. From here, thereare widespread connections to the cingulate gyrus. In the aforementionedOCD model, there are numerous connections to the Papez circuit via theDM nuclei and the OFC. These connections could subserve theanxiety/emotional component of OCD.

By synthesizing these three components, OCD symptoms could occur when anaberrant positive-feedback loop develops in the reciprocally excitatoryfrontothalamic neuronal pathway that is inadequately inhibited/modulatedby striatopallidothalamic activity. OCD symptoms would thus be expectedto appear when striatopallidothalamic activity is abnormally decreasedor when orbitofrontothalamic activity is abnormally increased.Conversely, either increasing the modulating loop or decreasing theexcitatory loop would be expected to result in a concomitant decrease inOCD symptom expression. Additionally, modulation of the Papez circuit,may in turn, remove some of the disturbing affect the obsessions orcompulsions have on a patient's emotional state. This mechanism isanalogous to the model of Parkinson's Disease in which dysregulation inthe corpus striatum, secondary to loss of dopaminergic transmission fromthe Substantia Nigra Pars Compacta (SNc), results in the increase intonic inhibition of the VL and VA thalamic nuclei by the internalsegment of the globus pallidus (Gpi).

Recent functional imaging studies have consistently found evidence thatcorroborate this model of OCD pathogenesis. Increases in activationcorrelating with OCD symptoms have been shown to occur in OFC, caudate,thalamus and cingulate areas. After treatment with appropriatemedications, including selective serotonin reuptake inhibitors (SSRI),and behavioral therapies, these areas of abnormally increased metabolismwere shown to decrease by PET and fMRI studies. Such areas of activationand responses to treatment might prove useful in assessing futureneurosurgical treatments for OCD.

The basal ganglia dysregulation has also been implicated in thepathoneurophysiology of Affective Disorders, including Major Depressionand Bipolar Disorder. Much of the work implicating the basal ganglia andother structures in the pathogenesis of Affective Disorders comes fromimaging studies using PET and fMRI. Abnormalities in metabolism havebeen demonstrated in the OFC, cingulate, basal ganglia, and amygdala.

In order to examine Affective Disorder from a neurophysiological pointof view, emotion can be divided into three components: an expressivecomponent (affect), an internal/representative component (mood), and amodulatory component. The expressive component of emotion, known asaffect, represents the external manifestation of a person's internalemotional state. This can further subdivided into two subcomponents:endocrine/humoral and skeletomotor. Connections between thecorticomedial amygdala and the hypothalamus via the stria terminalisregulate the release of cortisol and epinephrine in relation toemotional stimuli. Basolateral amygdala connections with the basalganglia directly influence skeletomotor motivation and behaviors inresponse to emotional stimuli.

The structures subserving the internal representation of an emotionalstate, known as mood, remains obscure. Experimental experience however,implicates the amygdala in conjunction with frontal/cingulate cortices,basal ganglia, and hippocampus. Certainly, the Papez circuit alsocontributes to this internal representation of emotional state. Thethird component represents a modulatory component between the expressiveand internal emotional states. Medial orbitofrontal cortex, cingulatecortex and the basolateral amygdala have all been heavily implicated inthis role. These three components can be condensed into a dual circuitmodel analogous to the one proposed for OCD. One, alimbic-thalamic-cortical loop consisting of the basolateral amygdala,the dorsomedial thalamic nucleus, and the medial and ventrolateralfrontal cortices runs in parallel with alimbic-striatal-pallidal-thalamic circuit, consisting of the ventralstriatum, the ventral pallidum, and the thalamus. It is possible thatAffective Disorder symptoms could be the result of an imbalance in theactivity between both of these circuits. Given the numerous connectionsbetween these two proposed circuits and the limbic system, the Papezcircuit must work in conjunction with these to fully express thesymptoms of Affective Disorder.

Various stimulation parameters are tested to assess side effects (suchas motor contraction, paresthesias, visual disturbance, pain, andautonomic modulation) or clinical efficacy. The electrical stimulationcan be applied to the patient's entire nuclei (pre-frontal cortex,orbitofrontal cortex, anterior limb of the internal capsule, NucleusAccumbens, ventral striatum, the ventral Pallidum anterior nucleus ofthe thalamus, dorsomedial nucleus of the thalamus, intralaminar thalamicnuclei, the cingulate cortex, Amygdala, Hippocampus, Mamillary bodies,the lateral hypothlamus the Locus Ceruleus, the Dorsal Raphe Nucleus,ventral tegmentum, the Substantia Nigra Pars Compacta and reticulata) orsubsections such as to one or more portions of the patient'sintralaminar nuclei. In addition to being applied to the patient'sintralaminar nuclei or portion thereof, the electrical stimulation canalso extend to other regions of the brain. Preferably, the electricalstimulation is applied only to the patient's intralaminar nuclei orportion thereof without stimulating other regions of the patient'sbrain. For example, the electrical stimulation can be applied to allportions of the patient's intralaminar nuclei except thecentromedian-parafasicularis, except the central lateral, or except boththe central lateral and centromedian-parafasicularis. Electricalstimulation can be epidural in case of prefrontal cortex andorbitofrontal cortex, or can be subdural or intraparenchymal.

The architecture of the brain provides a substantial advantage in thesearch for a general solution to undesirable neuronal activity. Thisdesign advantage takes the form of a centralized signaling nexus throughwhich many of the brain's disparate functions are channeled in anorganized and predictable manner. More particularly, the thalamus iscomprised of a large plurality (as many as one hundred or more) ofneuronal bundles or nuclei, as well as white matter tracts (highways ofinformation) which receive and channel nerve activity from all areas ofthe nervous system and interconnects various activities within thebrain. The thalamus is analogous to a centralized train station such asa grand central station. Many different train tracks come together, andmany trains carrying many different cargoes enter and exit; however, ifone has a schedule and a map, it is easy to find all the trains thatcarry coal because all coal carriers are routed through the same tracks.

In other words, in the thalamus, all the brain signals travel in anorganized fashion. The activity in the peripheral areas of the brainwhich are associated with the same, or similar conditions, are channeledthrough the same areas of the thalamus. In this way, the thalamus actsas a train relay station, or as a post office, re-routing disparatesignals along similar paths when the appropriate outcomes of theoriginal signals are similar.

It is this observation that would appear to permit the treatment ofcommon neurological disorders, particularly psychiatric disorders, bybrain stimulation of one specific area, rather than having to customizethe (gross) placement of the stimulator and/or catheter for eachpatient. For every one ascending connection from the thalamus to thecortex, there are 40 descending connections from the cortex to thethalamus. Thus, any abnormality in the cortex from various diseases canbe manifested in the thalamus and thus the thalamic nuclei may be usedfor intervention.

As is shown in FIGS. 1, 3, and 4, the anterior thalamic nuclei arecoupled most directly to the frontal lobes and the dorsomedial thalamicnucleus is coupled most directly to the orbitofrontal cerebral cortexwhich is most associated with personality and behavior. The orbitalfrontal cortex (OFC) is particularly implicated in the pathogenesis ofvarious psychiatric diseases. There are two main loops connecting thedorsomedial nucleus and the OFC. A direct, reciprocally excitatory loopis mediated by the neurotransmitter glutamate. An indirect, modulatoryloop occurs via connections through the ventromedial striatum and globuspallidus, and is thought to be mediated by multiple neurotransmittersincluding GABA, dopamine, and serotonin.

Referring more particularly to FIG. 1 the orbitofrontal cerebral cortex(201) consists of a subsection of the frontal cerebral cortex (203), themost anterior portion of the brain. Specifically, the orbitofrontalcortex lies medially to the inferior frontal gyrus and lateral to thegyrus rectus. The orbitofrontal cortex (OFC) is also distinctcytotechtonically, according to the widely accepted classificationscheme of Brodmann. The anatomic connections of the OFC with dorsomedialand anterior thalamic nuclei, the striatum, the pallidum, and the Papezcircuit (which is thought to mediate emotional affect in man) areillustrated in a conceptual map provided as FIG. 4. These circuits areall interconnected to each other as well as to the thalamus (anteriornucleus, dorsomedial nucleus, intralaminar nuclei), the basal gangliaand the limbic system (amygdala, hippocampus, cingulate gyrus).

The thalamus, which is a central integrating structure also contains theintralaminar nuclei. The ILN is schematically illustrated in FIG. 3 andthe XYZ coordinates are provided in the table shown in FIG. 6. The ILNhave diff-use projections to the various structures implicated inpsychiatric activity/disorders as is illustrated for example in FIG. 2.In looking at other aspects of the neural circuitry underlyingpsychiatric disorders, reference is made to FIG. 3. As shown in FIG. 3,within the intralaminar nuclei 102 are principally the anterior 104,midline 106, and posterior 108 subgroups. The anterior subgroups 104include the central lateral (CL) and paracentralis regions. Theposterior subgroups 108 include the centromedian-parafasciculariscomplex (Cm-Pf). The midline 106 and other related subgroups include thecentre medial (CM) nuclei and paraventricularis (Pv).

FIG. 6 shows the ILN subdivisions and their projection targets as wellas the stereotactic X (Medial-lateral), Y (anterior-posterior) and Z(superior-inferior) coordinates of these structures. Accordingly, basedon the table in FIG. 6, as an example, it can be deduced thatstimulation of the anterior subdivision 104 and more specifically, theparacentralis nuclei can influence the abnormal activity in theorbitofrontal cortex manifesting in anxiety disorders such as OCD.Similarly, it can be deduced that stimulation of the midline ILN 106 canaffect the limbic circuit and thus influence abnormal activity in mooddisorders such as major depression. This is but a few examples of theutility of the present invention using the ability to modulate ILN toaffect the various disruptions in the projected regions of the brain.

FIG. 2 shows the ILN nuclei and their interconnections to the variousstructures involved in the psychiatric circuitry. The intralaminarnuclei have important anatomical and physioloigcal connections thatinvolve the circuitry of psychiatric disorders. Intralaminar nuclei area small set of nuclei located in the paramedian thalamus. Theintralaminar nuclei can be divided into an anterior group and aposterior group. FIG. 3 illustrates the anatomical connections of theintralaminar nuclei (“ILN”) with distributed circuits underlyingarousal, attention, intention, emotions, working memory, and gaze andmotor control. The anterior ILN group projects widely throughout theneocortex to primary sensory and motor areas and association cortices,while the posterior group projects mainly to sensory-motor and premotorareas and striatal targets. The anterior ILN group includes the centrallateral nucleus (“CL”), which projects to the frontal eye field (“FEF”),motor cortex, and, more heavily, to the posterior parietal cortex(“PPC”). The paracentralis (“Pc”) nucleus projects to the prefrontalcortex (with heavier projection than CL) and very strongly to theinferior parietal lobe and visual association cortices. The centralmedial (“CeM”) nucleus, which also projects to the prefrontal and visualassociation cortices, also projects to the cingulate cortex andpregenual areas and to the medial cortical surface and orbitofrontalcortex. Included within the meaning of intralaminar nuclei, as usedherein, is the Paraventricular nucleus (“Pv”), which is stronglyassociated with the limbic system, and midline thalamic nuclei.Projections to prefrontal cortex (“IPFC”) and anterior cingulate cortexarise, as well, from the anterior intralaminar group. The CL is alsoknown to project to the primary visual cortex in the cat and monkey. Theposterior ILN group is dominated by the centromedian-parafasiculariscomplex (“Cm-Pf”), which strongly projects to areas 6 and 4. Inprimates, the CmPf undergoes a notable expansion, and the CL alsoexpands and develops further subdivisions. This system projects stronglyto the caudate (from Pf), putamen (from Cm nuclei of the basal ganglia),and prefrontal and parietal association cortices. A small projection(Pf) also goes to the FEF. The intralaminar nuclei projections to thestriatum per se are considered the principle efferent connections of theintralaminar nuclei and include anterior group projections to thecaudate, as well. While not wishing to be bound by theory, it wouldappear then that the intralaminar nuclei (including the midline nuclei)is in a preferred position to modulate the large thalamo-cortical-basalganglia loops, especially to synchronize their function.

Referring more particularly to FIG. 3, the anterior thalamic nuclei 100are located in the most anterior portion of the thalamus and areinterconnected with the frontal lobes. The intralaminar nuclei 102 arelocated in the paramedian thalamus (dividing each of the lobes of thethalamus along a Y shaped vertical planar geometry which cuts throughthe posterior to anterior axis of each lobe). The intralaminar nuclei102 have more diffuse projections. Together these nuclei groups are themost likely associated with psychological disorders. Referring now toFIG. 3, within the intralaminar nuclei 102 are principally the anterior104, midline 106, and posterior 108 subgroups. The anterior subgroups104 include the central lateral (CL) and paracentralis regions. Theposterior subgroups 108 include the centromedian-parafasciculariscomplex (Cm-Pf). The midline 106 and other related subgroups include thecentre medial (CeM) nuclei and paraventricularis (Pv).

The anterior thalamic nuclei are coupled most directly to the frontallobes or Orbital Frontal Cortex (“OFC”) which are most associated withpersonality and behavior. The posterior subgroup of the intralaminarnuclei, including the centromedian-parafascicularis, is coupled mostdirectly to the prefrontal, permotor, and parietal cortices. Theanterior subgroup, including the central lateral and paracentralisnuclei, is most directly connected to the parietal, visual association,prefrontal, frontal, and superior temporal cortices as well as thefrontal eye field. The midline and related intralaminar subgroups,including the paraventricularis, centre medial, midline nuclei, areconnected to the orbital frontal cortex, the hippocampus, the limbiccortex, and the amygdala.

The intralaminar nuclei receive ascending inputs from several componentsof the ascending reticular arousal system, including thepedunculopontine cholinergic group (lateral dorsal tegmentum),mesencephalic reticular formation, locus ceruleus, and dorsal raphe.Thus, the intralaminar nuclei are targets of modulation by a widevariety of neurotransmitter agents, including acetylcholine(pendunculopontine, lateral dorsal tegmentum, and mesencephalicreticular formation neurons), noradrenaline (locus ceruleus) serotonin(raphe nuclei), and histamine (hypothalamus). Also received by theintralaminar nuclei are nociceptive, cerebellar, tectal, pretectal, andrhinencephalic inputs. Descending inputs reciprocally relate componentsof the intralaminar nuclei with their cortical projections.

Although each cell group within the intralaminar nuclei projects to manyseparate cortical targets, each neuron of the intralaminar nuclei has anarrowly elaborated projection and receives its cortical feedback fromthe same restricted area. The reciprocal projections between theintralaminar nuclei and cortex have a distinctive laminar pattern thatdiffers from the more well-known pattern of the reciprocal projectionsof the relay nuclei. The intralaminar nuclei neurons synapse in Layer Ion the terminal dendritic tufts of layers III and V pyramidal cells andin layers V and VI, whereas neurons of the relay nuclei terminateprimarily in cortical layers III and IV. Feedback to intralaminar nucleineurons originates in Layer V, but feedback to the relay nucleioriginates in Layer VI. In the cat, the dominant corticothalamic inputto the CL originates in the PFC, whereas the visual areas, includingarea 17, also project directly to the CL.

As used herein, intralaminar nuclei also include paralamellar regions,such as parts of the medial dorsal (“MD”) nucleus and the midline nuclei(which are sometimes distinguished from the intralaminar nuclei but, forpurposes of the present application, are not). The exact location of thethalamic nuclei and their corresponding cortical connections can bedetermined via stereotactic techniques. Stereotactic techniques areroutinely used to triangulate and precisely locate structures which areidentified via specific coordinates, usually determined with respect totwo standard centralized brain landmarks called the anterior commisure(AC) and the posterior commissure (PC). This is analogous to a globalpositioning system that can determine the precise location ofindividuals.

The intralaminar nuclei in particular project to all the components ofthe psychiatric circuits described above. Thus, stimulation of theintralaminar nuclei (either all or any or combination) can affect thespecific components of the structures involved in the psychiatriccircuitry described above. Although one aspect of the present inventionis to stimulate a pre-determined area of the brain to impact thepsychiatric disorder described above (e.g. OCD or Anxiety disorder), apreferred embodiment of the present invention is to stimulate apre-determined area or areas of the ILN to have affect the connectedregion of the brain. A further aspect of this embodiment may be thedetection via sensors in one portion of the brain and stimulation in theILN to affect or impact the portion of the brain so indicated. As anexample, if an OCD event is detected in the orbital frontal cortex,stimulation may occur in the area of the ILN associated with the orbitalfrontal cortex

The method of the present invention can further comprise selecting oneor more subdivisions of the patient's intralaminar nuclei forstimulation. In particular, the subdivision to be stimulated can be onethat modulates the specific function that is impaired in the patient.

As indicated above, stimulation can be applied to an entire region, to agroup of nuclei or to one, two, or more specific subdivisions thereof.Stimulation can be applied to the one, two, or more specificsubdivisions in either or both brain hemispheres. In some cases, it canbe advantageous to apply electrical stimulation to two or moresubdivisions of the intralaminar nuclei that modulate separate corticalregions. Stimulation may be electrical, chemical, or both. As usedherein, cortical regions are considered to be separate when they are notcontiguous on the cortical mantle or they are considered separate infunction based on known anatomical or physiological characteristics ofcells within their borders. For example, the patient's central medialand centromedian-parafasicularis intralaminar nuclei subdivisions, whichrespectively project strongly to the orbitofrontal and premotor regionsof the cortex, can be stimulated.

Where two or more subdivisions of the intralaminar nuclei arestimulated, both can lie in the same thalamus. Alternatively, at leastone of the two or more subdivisions of the intralaminar nuclei can liein the left thalamus while at least one of the two or more subdivisionsof the intralaminar nuclei lies in the right thalamus. Preferably, atleast one of the two or more subdivisions and, more preferably, at leasttwo of the two or more subdivisions of the intralaminar nuclei to whichelectrical stimulation is applied modulates the specific cognitivefunction which is impaired in the patient.

With regard to a chemical based system, the drug-delivery pump may beprogrammed with an initial nominal dose scheme. Examples of suitablepharmaceutical agents that can be used in conjunction with theelectrical stimulation methods of the present invention include knownexcitatory and inhibitory transmitters that influence intralaminarnuclei function. Excitatory transmitters would preferably includeacetylcholine (“Ach”), noradrenaline (“NE”), and/or serotonin (“5-HT”)or analogues thereof. Inhibitory transmitters would include primarygamma-aminobutyric acid (“GABA”) or analogs thereof. Other amino acidtransmitters know to affect the intralaminar nuclei, such as adenosineor glutamate, can also be used.

Psychiatric disorders treated by electrical stimulation and/orpharmacotherapy, however, may take up to six months to demonstrateclinical efficacy. Long term adjustment of the signal or dosage beingapplied by the power source or drug-delivery pump may be required tooptimize the outcome. If the patient's symptoms do not subside, thesurgeon will attempt to adjust all of the parameters until they do.

Typically, the proximal end of the probe, is connected to remotelylocated signal source generator, subcutaneous drug pump or sensorprocessor (hereafter referred to generally as “remote device”) disposedwithin the patient's body. A specially designed plastic cap is generallyprovided to seat in the burr hole, and permit the proximal end of theprobe to pass out through the skull. The incision in the patient's skullis then sutured closed with the probe temporarily stored under the skin.If the patient is not already under general anesthesia, the patient isso disposed and a tunnel is formed under the dermal layers, connectingthe incision in the scalp to the remote location, usually theinfraclavicular region, beneath the collar bone—where cardiovascularpace makers are implanted. Subsequently, the probe is joined to acoupling extending from the remote device. Generally, the manner inwhich the probe and the remote device are coupled utilizes the sameterminal contacts as would be used for direct coupling to the powersource.

Once the surgery is complete, a non-contrast CT scan is taken to ensurethat there is no intracranial hematoma. Subsequently, variousstimulation parameters are programmed and patients are assessed for anyside effects as well as clinical efficacy. As behavioral and relatedcognitive improvement may not occur immediately, long-term benefits maynot be achieved until multiple adjustments are accomplished.

Where two or more subdivisions of the patient's brain (e.g. intralaminarnuclei) are electrically stimulated periodically and at the samefrequency, such stimulation can be completely in phase, partially inphase and partially out of phase, or completely out of phase. When suchstimulation is substantially entirely in phase, it is said to besynchronized. In a preferred embodiment of the present invention, theelectrical stimulation applied to two or more subdivisions of thepatient's intralaminar nuclei is synchronized.

While there has been described and illustrated specific embodiments ofnew and novel methods of treatment for neurological disorders, it willbe apparent to those skilled in the art that variations andmodifications are possible without deviating from the broad spirit andprinciple of the present invention which shall be limited solely by thescope of the claims appended hereto.

Having thus set forth the preferred embodiments, the invention is nowclaimed to be:
 1. A method of treating a disorder associated with aspecific area in a brain comprising: implanting a device in contact withan intralaminar nuclei of the brain; sensing activity in the specificarea of the brain, wherein the specific area of the brain is differentthan the intralaminar nuclei, and wherein the specific area of the brainis different than the intralaminar nuclei and the sensing activityoccurs at a location distal from the device location; and operating thedevice to modulate the intralaminar nuclei in response to said activityto thereby affect the disorder associated with the specific area of thebrain.
 2. The method of claim 1, wherein the device is an electrodeassembly.
 3. The method of claim 1, wherein the activity being sensed iselectrical activity.
 4. The method of claim 1, wherein the device issustained-release matrix.
 5. The method of claim 1, wherein saidspecific area is selected from the group consisting of the pre-frontalcortex, orbitofrontal cortex, anterior limb of the internal capsule,Nucleus Accumbens, ventral striatum, the ventral Pallidum anteriornucleus of the thalamus, dorsomedial nucleus of the thalamus,intralaminar thalamic nuclei, the cingulate cortex, Amygdala,Hippocampus, Mamillary bodies, the lateral hypothalamus, the LocusCeruleus, the Dorsal Raphe Nucleus, ventral tegmentum, the SubstantiaNigra Pars Compacta and reticulata.
 6. The method of claim 1, whereinsaid disorder is selected from the group consisting of obsessivecompulsive disorder, generalized anxiety disorder, post traumatic stressdisorder, panic attacks, social phobia, major depression, bipolardisorder, schizophrenia, and substance abuse disorders/additions.
 7. Themethod of claim 1, wherein said step of sensing occurs epidurally,subdurally, or on the scalp.
 8. The method of claim 1, wherein said stepof sensing occurs at the local milieu of the electrode.
 9. A method ofaffecting a psychiatric activity in a specific area of the braincomprising: placing an electrode in contact with an intralaminar nucleiof the brain; and operating the device to provide stimulation to theintralaminar nuclei to thereby affect the psychiatric activity in thespecific area of the brain, the specific area of the brain beingdifferent than the intralaminar nuclei.
 10. The method of claim 9,wherein the stimulation is electrical.
 11. The method of claim 10,wherein the device is an electrode assembly.
 12. The method of claim 9,wherein the stimulation is chemical.
 13. The method of claim 12, whereinthe device is a sustained-release matrix.
 14. The method of claim 9,wherein said specific area is selected from the group consisting of thepre-frontal cortex, orbitofrontal cortex, anterior limb of the internalcapsule. Nucleus Accumbens, ventral striatum, the ventral Pallidumanterior nucleus of the thalamus, dorsomedial nucleus of the thalamus,intralaminar thalamic nuclei, the cingulate cortex, Amygdala,Hippocampus, Mamillary bodies, the lateral hypothalamus, the LocusCeruleus, the Dorsal Raphe Nucleus, ventral tegmentum, the SubstantiaNigra Pars Compacta and reticulate.
 15. A method of affectingpsychiatric activity in a patient comprising: identifying a portion ofthe patient's ILN intralaminar nuclei which is in communication with apredetermined region of the patient's brain, said predetermined regionof said patient's brain being associated with the psychiatric activity;and modulating the portion of the patient's ILN to effectuate thepsychiatric activity.
 16. The method of claim 15, wherein theidentification of a portion of the patient's intralaminar nuclei isbased upon a composite of other patient's intralaminar nuclei activity.17. The method of claim 15, wherein the identifying step is independentof an exhibition of a pathologic condition in the predetermined regionof said patient's brain.
 18. The method of claim 15, wherein thepsychiatric activity is selected from the group consisting of happiness,fear, anger, anxiety, euphoria, and sadness.
 19. The method of claim 15,wherein the modulation of the portion of the patient's ILN isaccomplished using chemical stimulation.
 20. A method of treating adisorder associated with specific area in a brain comprising: implantinga device wherein the device includes a sustained release matrix incontact with an intralaminar nuclei of the brain; sensing activity inthe specific area of the brain, wherein the sensing activity occurs at alocation distal from the device location; and operating the device tomodulate the intralaminar nuclei in response to said activity to therebyaffect the disorder associated with the specific area of the brain. 21.The method of claim 20, wherein modulation occurs via release of achemical from the sustained release matrix.
 22. The method of claim 20,wherein the specific area of the brain in which the device is implantedis different than the intralaminar nuclei.
 23. The method of claim 17,wherein said step of sensing occurs epidurally, subdurally, or on thescalp.